The compound of the general formula (I,) where R is hydrogen and n is 0 [N-Methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine hydrochloride; Fluoxetin] is used in medicine as a selective inhibitor of serotonine uptake (Wong, D. T., et al., Drug Dev. Res., 1985, 6.397) and in the treatment of depressions and various types of psychical and metabolic disorders (Chovinard, G. A., Clin. J. Psychiatry, 1985.46 32.
Preparation of Fluoxetin is described in the U.S. Pat. Nos. 4,018,895, 4,194,009 and 4,314,081, British Patent 2,060,618, Spanish Patent 556,009 and European Patent Applications (A1) 0 380 924 and 0 391 070.
According to the U.S. patent by bromination of 3-chloropropylbenzene (II) with bromosuccinimide 1-bromine-3-chloropropylbenzene (III) is prepared, which is then by the reaction with p-trifluoromethylphenole converted to N-methyl-(p-trifluoromethylphenoxy)-3-phenylpropylchloride (IV), from which fluoxetin (I) by the reaction with methylamine is obtained.
Yields in the last two phases are moderate, irrespective of the mode in which the process is carried out. Transformation of the compound (IV) into Fluoxetin requires high reaction temperatures at which several by-products are produced, which reduces the yield significantly and creates a considerable problem in obtaining pure product by crystallization.
Significant difficulties also arise during the large scale production which applies another described procedure involving N,N-dimethyl-3-(p -trifluoromethylphenoxy)-3-phenylpropylamine (V) as an intermediate, especially because of the use of bromine cyan as a demethylation agent which is very dangerous under the production conditions. Similarly, yields at some phases of this procedure, according to the statements of EP Appl. 0 391 070 (A1) are very low, approximately 20%.
In the Spanish Patent 556 009, N-acyl and N-alkylcarbalcoxy derivatives of N-methyl-3-phenyl-3-hydroxypropylamine (VI) as intermediates are used, which by the treatment with methylsulfonylchloride are converted into the corresponding methylsulfonyl derivative (VII). After the reaction VII with p-trifluoromethylphenol N-methyl-N-acyl (i.e., alkylcarbalcoxy)-3-(p -trifluoromethylphenoxy)-3-phenylpropylamines (VIII) are obtained, from which Fluoxetin (I) by the acid hydrolysis is prepared.
This procedure too is rather inappropriate for preparation of fluoxetin because it is quite certain that the preparation of starting intermediate (VI), for which there is no indication as of its mode of preparation, requires at least three reaction stages. Furthermore, the compound (VII) is rather unstable, and after all the yields at some phases are in general unsatisfactory. We have experimentally shown that by acid hydrolysis of the compound (VIII), prepared according to the procedure of this invention and under the conditions given in this patent, practically major part of the substance has not been affected by the reaction, and that Fluoxetin has been detected only by thin layer chromatography.
Recently published European Patent Application 0 380 924 (A1) describes preparation of Fluoxetin, where the starting material is ethyl benzoylacetate (IX), from which by the reduction with metal hydrides 3-hydroxy-3-phenylpropionate (X) is obtained. By further reaction with methylamine, it is transformed into N-methylamide 3-hydroxy-3-phenylpropionic acid (XI). This compound (XI) is converted with p-trifluoromethylphenol in the presence of the activating substances to 3-phenyl-3-(p-trifluoromethylphenoxy)-N-methyl propanamide (XII). After the reduction with metal hydrides it gives Fluoxetin (I).
The disadvantage of these procedures is in that, like in already described procedures, one of the starting compounds is the extremely costly p-trifluoromethylphenol (whereas the procedure given in this invention uses much cheaper p-trifluoromethylchlorbenzene), and that it is very unsuitable for the large scale production because of the use of LiAlH.sub.4.
In the British Patent 2,060,618 and EP Application 0 391 070 (A1), the starting intermediate is N-methyl-3-phenyl-3-hydroxypropylamine (XIV). Its preparation is described only in the aforementioned EP Appl. and is done by the reduction of b-N-benzyl-N-methylaminopropyophenone (XIII) with hydrogen and Pt-Pd/C as a catalyst. Fluoxetin (I) is produced by the reaction of the compound (XIV) with p-trifluoromethylfluorbenzene in dimethylsulfoxide and NaH (Brit. pat.), i.e., with p-trifluoromethylchlorbenzene in N-methylpyrrolidinone with potassium-terc. butoxide (EP Appl.).
Disadvantage of these procedures is that in the first case one of the starting raw materials is p-trifluoromethylfluorbenzene, which is approximately ten times as expensive as p-trifluoro-methylchlorbenzene. In the second case, the yields at the second phase, according to our experience, are almost by 30% lower than stated in the patent application.
The compounds of the general formula (I), where R is aryl and alkylaril group, and where n is 0 and 1, can be used as intermediates for preparation of Fluoxetin and other pharmacologically active substances.